Leishmaniasis affects large numbers of people in Africa, Asia, Europe and Latin America. Drugs which are currently used for its treatment are association with serious side-effects and relapse of disease may occur. The proposed project outlines attempts to develop new leishmanicidal drugs. We hope to accomplish this by first identifying key points in the metabolism of the parasite which differ from man. Attempts will then be made to find agents which take advantage of these differences to selectively poison the parasite with minimal host toxicity. Biochemical studies will include investigations of the oxidative metabolism, peroxide metabolism and cell surface of leishmania. In addition, the effect of intracellular leishmania on host cell biochemical pathways will be ascertained. The outcome of these biochemical studies will then direct the selection of pharmacological agents. For example, there is some evidence that leishmania lack catalase. In this case, they would be similar to T. brucei bloodstream forms and be vulnerable to lysis by compounds such as porphyrines, which react with H2O2 to form free radicals. We have obtained preliminary results which show that porphyrins are leishmanicidal in vivo. Our work will also include the screening of promising compounds in vitro and in vivo in leishmania infected mice.